Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis

Abstract

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-a and interferon-c in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. (Cancer Sci 2011; 102: 1403-1409 L ung metastasis is the most common cause of cancer death in both men and women. Investigators have done a lot to improve its prognosis and the development of new modalities of treatment. Gene therapy is a promising and powerful method; currently, its potential in cancer treatment is widely recognized. However, the major limitation of gene therapy of the lung is the low efficiency of gene transfer and the technical difficulties of regimen delivery.(1) Delivery vectors play an important role in gene therapy because the plasmid DNA must be protected from damage and its entry into the cell must be facilitated. Some polymers and cationic lipids have shown high gene transfection efficiency in the lung for DNA encapsulated.(2) The cationic polymer polyethylenimine (PEI) has the ability to protect DNA from undesirable degradation during the transfection process and is one of the most effective non-viral gene vectors. (3)(4)(5) However, PEI also has a shortcoming: the increase in transfection efficiency is accompanied by an increase in cytotoxicity, and both efficiency and cytotoxicity increase as its molecular weight increases. To address this challenge, we used heparin to couple PEI together, forming HPEI nanogels; these nanogels had high transfection efficiency and low toxicity, showing promising application as a non-viral gene delivery system. (6) Interleukin-15 (IL15) is a cytokine first identified in the supernatant of the monkey epithelial cell line CV-1 ⁄ EBNA and has a simila...

Gene therapy for C-26 colon cancer using heparin-polyethyleneimine nanoparticle-mediated survivin T34A

“…The results have shown HPEI nanoparticles to be a novel nonviral gene carrier with promising application in cancer gene therapy. 29,48 In this work, we prepared a plasmid-expressing ms-T34A gene and used HPEI nanoparticles to deliver this gene to treat colon cancer in vitro and in vivo. The anticancer effect of HPEI nanoparticle-mediated ms-T34A gene therapy was evaluated, and the relevant anticancer mechanisms are discussed.…”

Progress in the development of Lipoplex and Polyplex modified with Anionic Polymer for efficient Gene Delivery

“…Anionic polymer or its conjugate Cationic polymer or liposome Reference pDNA ᵞPGA Chitosan [66,67] pDNA ᵞPGA Dendrigraft poly-L-lysine [80] pDNA ᵞPGA PEI [81][82][83] pDNA ᵞPGA Protamine [75] pDNA αPGA DOTAP/Chol liposome [54] siRNA ᵞPGA Chitosan [73] siRNA ᵞPGA Dendrigraft poly-L-lysine [74] siRNA αPGA DOTAP/Chol liposome [77] siRNA αPGA DMAPAP/DOPE liposome [78,79] siRNA ᵞPGA PEI [76] pDNA Heparin Cationic glycopolymer (Tr4) [84] pDNA Heparin-PEI - [85] pDNA Alginic acid, Pectin Lipofectamine 2000 [24] pDNA: plasmid DNA, siRNA: small interfering RNA, ᵞPGA: poly-ᵞ-glutamic acid, αPGA: poly-α-glutamic acid, PEI: polyethylenimine, DMAPAP: 2-{3-[bis-(3-amino-propyl)-amino]-propylamino}-N-ditetradecyl carbamoyl methylacetamide, Chol: cholesterol, DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine.…”

“…They speculated that heparin coating of the polyplexes appeared to improve cell surface binding, internalization, intracellular traf icking of polyplexes to the nucleus, leading to high transgene expression. Furthermore, chemically conjugated PEI with heparin (heparin-PEI) formed a nanogel, and intravenous injection of heparin-PEI and pDNA complexes ( Figure 5B) exhibited high distribution of pDNA in the lung, and inhibited lung metastasis of malignant melanoma B16-F10 and mouse colon carcinoma Colon 26 by injection of pDNA encoding interleukin 15 gene [85], indicated that the heparin-PEI conjugate is an ef icient gene carrier to the lung.…”

Emerging applications of nanoparticles for lung cancer diagnosis and therapy

“…They used heparin-conjugated PEI for the delivery of therapeutic gene pIL15 (encoding interleukin-15) in murine models of lung metastasis. The post-treatment therapeutic assessment indicated apoptosis and inhibition of cell proliferation in lung tumor foci, which could curb the growth of cancer cell mass to a great extent [57].…”